Amyloid plaques, which appear to be mainly composed of beta amyloid peptides (Aβ), are found in Alzheimer's disease, some variants of Lewy body dementia, and inclusion body myositis. Aβ aggregates are also found to coat cerebral blood vessels in cerebral amyloid angiopathy. The Aβ peptide is derived by proteolysis of a larger membrane-bound β-amyloid precursor peptide (Haass and Selkoe, 1993).
The most well known disease involving amyloid plaques is Alzheimer's disease (AD), an irreversible, progressive brain disease that slowly destroys memory and thinking skills. AD is the most common cause of dementia among older people, but it is not a normal part of aging. AD starts in a region of the brain that affects recent memory and then gradually spreads to other parts of the brain. Damage to the brain may begin as many as 10-20 years before any obvious signs of forgetfulness appear. As nerve cells die throughout the brain, affected regions begin to shrink. By the final stage of AD, damage to the brain is widespread. According to the U.S. National Institute on Aging, 2.4 to 4.5 million Americans currently have AD. Projections using current population trends suggest that the number of Americans with AD will increase significantly. This increase of AD patients will not only affect their families, but will also put a heavy economic burden on society unless more effective treatments can be found.
Although a consensus on the primary mechanisms that cause neuronal damage in AD remains elusive, numerous reports have associated the cytotoxicity of Aβ peptides with the neurodegeneration observed in specific brain areas of AD patients (Yankner, 1996; Yankner, 2000; Hardy and Higgens, 1992, Hardy and Selkoe, 2002). It has been shown that addition of fresh aggregates of Aβ to cell cultures generates a potentially toxic increase in the intracellular calcium concentration (Mattson et al., 1992; Kawahara et al., 2000; Zhu et al., 2000; Demuro et al., 2005; Simakova and Arispe, 2006). Years of research support the concept that disturbances of intracellular calcium homeostasis may play a pathological role in the neurodegeneration associated with AD (Mattson et al., 1993; Kawahara, 2004; LaFerla, 2002; Smith et al., 2005).
A mechanism for the Aβ peptide-induced increase in intracellular calcium was originally proposed based on the formation of an independent tromethamine and aluminum-sensitive Aβ channel (Arispe et al., 1993). This Aβ channel, which permits the entrance of extracellular calcium ions into the cell (Arispe et al., 1994; Aripse et al., 2007), has been confirmed in a variety of membranes by many researchers over the past decade (Kawahara et al., 1997; Rhee et al., 1998; Lin et al., 1999; Kourie et al., 2001; Kagan et al., 2002), has been observed with atomic force microscopy (Quist et al., 2005; Lal et al., 2007), and has been subjected to theoretical modeling (Durrell et al., 1994; Jang et al., 2007; Jang et al., 2008). The asymmetry in one of the models (Durrell et al., 1994) explains the finding that zinc preferentially binds and blocks only one side of the Aβ channel (Arispe et al., 1996). It has been frequently demonstrated in studies of different metalloproteases, as well as in the Aβ molecule, that sites rich in Histidine (His) and anionic residues are associated with Zn2+ binding (Chakrabarti, 1990; Perlman and Rosner, 1994; Becker and Roth, 1993; Miura et al., 2000; Yang et al., 2000). Because of the unique chemical nature of the His residue, it has a strong metal affinity. His residues act as a ligand to a metal center (Mukherjee and Bagchi, 2006) bridging imidazole groups from the side chains of His residues (Yang et al., 2000). In the theoretical models of Durell et al. (1994), the least energy calculations for the full size Aβ channels, imbedded in a lipid environment, position the rings of His13 and His14 of the Aβ molecule around the entrance of the putative pore. To test this prediction for the modeling algorithm, it has recently been shown that peptide fragments of Aβ containing the two neighboring His13 and His14 residues effectively block Aβ channel activity in planar lipid bilayers (Arispe et al., 2007; Aripse, 2004; Diaz et al., 2006). When the His-His diad is substituted with residues lacking a propensity to interact with His residues, the Aβ-derived peptides lose their effectiveness to both block the Aβ channel and to prevent Aβ peptide cytotoxicity (Diaz et al., 2006). Furthermore, methylation of the imidazole side chains of His residues in the Aβ-derived peptide prevents the formation of His bridges, and also results in abolition of Aβ peptide neurotoxicity (Tickler et al., 2005).
Although progress has been made in evaluating Aβ-derived peptides that can block the Aβ channel and prevent Aβ peptide cytotoxicity, these peptides represent fragments of the Aβ polypeptide and thus present potential limitations as therapeutic molecules, including possible interactions with other natural molecules, such as the β-amyloid precursor protein, and resistance to crossing certain natural barriers, such as the blood brain barrier.